1. Field of the Invention
The present invention relates to derivatives of epipodophyllotoxin, their use as antitumor agents, and pharmaceutical compositions containing them. More particularly, the novel compounds of the present invention are acyl derivatives of 4'-demethylepipodophyllotoxin glucosides.
2. Description of Background Art
Etoposide and teniposide are clinically useful anti-tumor agents derived from the naturally occurring lignan, podophyllotoxin. Currently etoposide is marketed in the United States under the trade name Vepesid for the treatment of small cell lung cancer and testicular cancer. The favorable pharmacological properties of etoposide and teniposide have encouraged much activity in the search for other active analogs within the same class.
4'-0-Demethylepipodophyllotoxin glucosides wherein the hydroxyl groups of the sugar moiety are acylated have been reported in the literature as intermediates for the preparation of the corresponding 4'-demethylepipodophyllotoxin glucosides; however, the phenol group of these compounds are also protected.
Canadian Patent No. 956,939 discloses compounds of formula (I) ##STR1## wherein R.sup.1 is C.sub.1-5 alkyl; R.sup.2 is acetyl or formyl; and R.sup.3 is phenyl or substituted phenyl; possible substituted phenyls mentioned but not exemplified are p-nitrophenyl and p-methoxyphenyl.
U.S. Pat. No. 4,564,675 discloses compounds of the formula (II) ##STR2## wherein R is --C(O)CH.sub.2 X, X is a halogen atom.
European Patent Application 162,701 discloses compounds of formula (III) ##STR3## Wherein R.sup.1 and R.sup.2 may be the same or different and each represent --C(O)CHX.sub.2 or --C(O)CX.sub.3 wherein X is a halogen atom.
Japanese Kokai 58/225,096 (Derwent Abst. No. 84-034268/06) and 58/219,196 (Derwent Abst. No. 84-027495/05) disclose compounds of formula (IV) and (V), respectively. ##STR4## wherein A stands for --CO.sub.2 --CH.sub.2 --C(H)m(X)n wherein X is a halogen atom and m is 0 to 2 and n is 1 to 3, m+n=3, and Ac is acyl.
European Patent Application 226,202 discloses an intermediate for etoposide synthesis having the formula (VI) ##STR5## wherein A represents an acetyl group.
Mono-hemisuccinate derivatives of etoposide having the formulas (VII) are reported in J. Pharm. Biomed. Anal., 1987, 5(1):11-20 ##STR6## wherein one of R.sup.1 and R.sup.2 is H and the other is --CO(CH.sub.2).sub.2 CO.sub.2 H. These compounds are used as a means to conjugate etoposide to bovine serum albumin.
4'-Phosphate of etoposide and the disodium salt thereof are disclosed in Japanese Kokai 63/192,793. ##STR7##